CD38是一个46kD的跨膜糖蛋白，同时具备受体和酶活性，能够催化细胞内钙离子信使cADPR和NAADP的合成与水解。研究表明，包括多发性骨髓瘤（MM）在内的多种肿瘤，其肿瘤细胞表面都有CD38的高表达，因此CD38是治疗MM的良好药物靶点，目前已经有一个单克隆抗体daratumumab被美国FDA批准用于MM治疗。

纳米抗体，也称作单域抗体，是抗体中能够结合抗原的最小片段，来源于骆驼科血液中自然存在的重链抗体。纳米抗体只有15kD，是传统抗体的十分之一。相对于传统抗体，纳米抗体具有一些优势：有良好的稳定性及可溶性，易于改造，生产成本低，能够识别隐藏的或不常见的抗原位点，能够促进抗体衍生物的发展，像免疫结合物、二价抗体等。

我们以CD38为靶标筛选出一系列纳米抗体，解析出纳米抗体与CD38的共晶结构。以这些纳米抗体为基础构建了荧光抗体，结合流式细胞技术发展了快速定量细胞表面CD38方法。进一步的，我们基于这些纳米抗体构建了针对CD38的免疫毒素，杀伤MM细胞的EC₅₀达pM水平，具有良好药效的同时具有高特异性和安全性。

CD38纳米抗体的开发为CD38信号通路机制研究和MM的诊断和治疗都提供了非常有价值的工具。

该工作第一作者是我组博士研究生黎婷，发表在Scientific Reports杂志上。

论文链接：http://www.nature.com/articles/srep27055

CD38, a 46kD transmembrane glycoprotein, is both a receptor and an enzyme which catalyzes the synthesis and hydrolysis of two calcium messengers cyclic ADP-ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate (NAADP). Research suggested that, CD38 expressed at extremely high level in some malignant cells including multiple myeloma (MM). Considering the huge differences of the expression between normal and myeloma cells, CD38 is thought to be a good drug target for cancer therapy and the first monoclonal antibody against CD38, daratumumab, has been approved by US FDA to be applied on MM treatment.

Nanobody (Nb), also refers as single-chain antibody, is the smallest capable intact antigen-binding antibody fragment that derived from heavy-chain antibody (HcAb) naturally existed in the serum of Camelidae. Nanobody is about 15kD, only tenth of conventional antibody. Compared to traditional antibody, nanobody has some advantages: the good stability and solubility, editing and construction easily, low expense of production, and the capability to recognize hidden or uncommon epitopes and easy to develop derivants, such as immune-conjugates, bivalent antibodies and so on.

We have obtained a series of nanobody targeting CD38, and elucidated the co-crystal structures of CD38 and the nanobodies. Based on these nanobodies, we constructed several chromobodies and developed a simple method to quantify the cell surface CD38, combining the flow cytometry. Furthermore, immunotoxins based on these nanobodies showed highly selective cytotoxicity against patient-derived MM cells as well as the cell lines with half maximal effective concentration reaching as low as pM.

These nanobodies are valuable tools for both basic researches on the molecular mechanism of CD38 signaling and theranostics of multiple myeloma.

The first author of the work is the PhD student Ting Li from our group. The paper was published in the Scientific Reports.

Article link: http://www.nature.com/articles/srep27055